Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central histaminergic system is one of the subcortical aminergic projection systems involved in several regulatory functions. The central dopaminergic and histaminergic systems interact extensively, but little is known about the histaminergic system in diseases affecting the dopaminergic neurons. The distribution of histaminergic fibers in the substantia nigra (SN) in postmortem brain samples from patients suffering from Parkinson's disease (PD) and normal controls was examined with a specific immunohistochemical method. Direct connections between dopaminergic neurones and histaminergic fibers were observed. Histamine in human SN was stored in fibers and varicosities. Sites of histamine formation were examined by l-histidine decarboxylase in situ hybridization. In both normal and PD brains HDC mRNA was found only in posterior hypothalamus and not in SN. The presence of histaminergic innervation of the human substantia nigra pars compacta (SNc) and reticulata (SNr), paranigral nucleus, radix of oculomotor nerve, and parabrachial pigmented nucleus was demonstrated. The density of histaminergic fibers in the middle portion of SNc and SNr was increased in brains with PD. In PD the morphology of histaminergic fibers was also altered; they were thinner than in controls and had enlarged varicosities. An increase of histaminergic innervation may reflect a compensatory event due to deficiency of, e.g., dopamine or a putative fiber growth inhibitory factor. Whether the changes seen in histaminergic fibers in PD are primary or secondary remains to be investigated.
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PMID:An altered histaminergic innervation of the substantia nigra in Parkinson's disease. 1078 40

Parkinson's disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Symptoms do not appear until most nigral neurons are lost, implying that compensatory mechanisms are present. Sprouting has been proposed as one of these mechanisms. This study quantified the extent of compensatory axonal sprouting following injury of dopaminergic neurons within the substantia nigra pars compacta. Specifically, the extent of the axonal arbour and axonal varicosity morphology was measured after partial destruction (with 6-hydroxydopamine) of the substantia nigra of the adult male rat. Four months later, the substantia nigra was injected with the anterograde neuronal tracer dextran-biotin to trace the full extent of individual axons. An unbiased estimate of neuron number was performed in each animal. This demonstrated nigral neuronal loss ranging from 10 to 90% on the side that received the injection whilst a 7% reduction was observed in the side contralateral to the lesion. Coincident with this loss, some nigral neurons lose tyrosine hydroxylase expression. Vigorous axonal sprouting was observed in the terminal arbours of lesioned animals and was associated with an increased axonal varicosity size. Axonal varicosities and branching points were primarily confined to the dorsal 1.5mm of the caudate-putamen, an area predominantly innervated by nigral neurons. It appears that dopaminergic neurons were responsible for this sprouting because the density of dopamine transporter immunoreactive varicosities in the caudate-putamen was maintained until about a 70% loss of neurons. It was concluded that substantial compensation in the form of sprouting and new dopaminergic synapse formation occurs following lesions of the substantia nigra pars compacta.
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PMID:Axonal sprouting following lesions of the rat substantia nigra. 1087 66

Interactions between apparently separate dopaminergic and glutamatergic pathways figure prominently in the pathophysiology of Parkinson's Disease. So it is surprising that the ventral midbrain dopamine neurons, which give rise to the dopaminergic pathway, may themselves also be glutamatergic. We have addressed this idea in both rat and monkey brain and found that most ventral midbrain dopamine neurons exhibit glutamate immunoreactivity. We used postnatal cell culture to examine ventral midbrain dopamine neurons more closely. In vitro most dopamine neurons exhibit glutamate immunoreactivity, as well as immunoreactivity for phosphate-activated glutaminase, the enzyme principally responsible for the synthesis of neurotransmitter glutamate; inhibition of glutaminase reduces glutamate staining. In single cell microcultures, dopamine neurons make both dopaminergic and glutamatergic synaptic varicosities. Stimulation of individual dopamine neurons evokes a fast excitatory synaptic response mediated by glutamate; it also evokes dopamine release that inhibits the excitatory response via presynaptic D2 receptors. Thus, dopamine neurons appear to exert rapid synaptic actions via their glutamatergic synapses and slower modulatory actions via their dopaminergic synapses, including possibly inhibition of their own glutamatergic synapses. So, in the setting of dopamine neuron demise, there will be a loss of both dopaminergic and glutamatergic inputs to the striatum; furthermore, glutamate released by dopamine neurons may contribute to an excitotoxic cascade and the death of neighboring dopamine neurons.
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PMID:Glutamate is a cotransmitter in ventral midbrain dopamine neurons. 1133 Nov 97

In the monograph of Santiago Ramon y Cajal, he provided a detailed description about the morphological changes in degeneration and regeneration of peripheral and central nervous systems following lesions. He discussed factors that may promote or inhibit axonal growth after peripheral and/or central nerve injury. Cajal with a brilliant insight anticipated the existence of several factors acting on degeneration and regeneration. Free radicals have been proposed to be one of such factors. These highly reactive oxygen species-derived free radicals play a pathogenetic role in neurological disorders, including ischemia, trauma, Alzheimer's disease and Parkinson's disease (PD). In this review we will discuss the similarities and differences between the morphological changes under oxidant stress and Cajal's drawings of degeneration and regeneration following the central injury. The monoaminergic neuron systems in the brainstem appear vulnerable to these free radicals, which have also been implicated in the selective degeneration of the nigrostriatal DA system. We analyzed the degeneration of fibers and the neuronal cell death of brainstem monoaminergic neuron systems in a mutant rat, which has abnormal metabolism of oxygen species in the brain. The degeneration of DA cell bodies and fibers was characterized by swollen varicosities and clustered fibers.
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PMID:Vulnerability of monoaminergic neurons in the brainstem of the zitter rat in oxidative stress. 1214 89

Two mutations in alpha-synuclein, the main constituent of Lewy bodies, have been identified in familial Parkinson's disease. We have stereotactically injected lentiviral vectors encoding wild-type and A30P mutant human alpha-synuclein in different brain regions (striatum, substantia nigra, amygdala) of mice. Overexpression of alpha-synuclein induced time-dependent neuropathological changes reminiscent of Lewy pathology: abnormal accumulation of alpha-synuclein in cell bodies and neurites, alpha-synuclein-positive neuritic varicosities and cytoplasmic inclusions that stained with ubiquitin antibodies and became larger and more frequent with time. After one year, alpha-synuclein- and ubiquitin-positive neurons displayed a degenerative morphology and a significant loss of alpha-synuclein-positive cells was observed. Similar findings were observed with both the wild-type and the A30P mutant form of alpha-synuclein and this in different brain regions. This indicates that overexpression of alpha-synuclein is sufficient to induce Lewy-like pathology and neurodegeneration and that this effect is not restricted to dopaminergic cells. Our data also demonstrate the use of lentiviral vectors to create animal models for neurodegenerative diseases.
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PMID:Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein. 1294 25

The substantia nigra pars reticulata (SNr) plays a key role in basal ganglia function. Projections from multiple basal ganglia nuclei converge at the SNr to regulate nigrothalamic output. The SNr is also characterized by abundant aminergic input, including dopaminergic dendrites and axons containing 5-hydroxytryptamine (5-HT) or histamine (HA). The functions of HA in the SNr include motor control via HA H3 receptors (H3Rs), although the mechanism remains far from elucidated. In Parkinson's disease, there is an increase in H3Rs and the density of HA-immunoreactive axons in the SN. We explored the role of H3Rs in the regulation of 5-HT release in SNr using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in rat midbrain slices. Immunohistochemistry identified a similar distribution for histaminergic and serotonergic processes in the SNr: immunoreactive varicosities were observed in the vicinity of dopaminergic dendrites. Electrically evoked 5-HT release was dependent on extracellular Ca2+ and prevented by NaV+-channel blockade. Extracellular 5-HT concentration was enhanced by inhibition of uptake transporters for 5-HT but not dopamine. Selective H3R agonists (R)-(-)-alpha-methyl-histamine or immepip inhibited evoked 5-HT release by up to 60%. This inhibition was prevented by the H3R antagonist thioperamide but not by the 5-HT1B receptor antagonist isamoltane. H3R inhibition of 5-HT release prevailed in the presence of GABA or glutamate receptor antagonists (ionotropic and metabotropic), suggesting minimal involvement of GABA or glutamate synapses. The potent regulation of 5-HT by H3Rs reported here not only elucidates HA function in the SNr but also raises the possibility of novel targets for basal ganglia therapies.
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PMID:Histamine H3 receptors inhibit serotonin release in substantia nigra pars reticulata. 1547 Jan 36

The putative dopaminergic (DA) neurons intrinsic to the human striatum were studied by applying immunofluorescence and quantitative methods to postmortem tissue from seven normal individuals. Stringent morphological and chemical criteria were used to identify striatal DA neurons, including immunostaining for tyrosine hydroxylase, DA transporter and neuronal nuclear protein. The DA neurons were scattered throughout the striatum, but abounded particularly in its ventral portion. Frequency distribution of surface areas of DA cell bodies reveals that the most frequent DA neurons (x =58.0%, S.D.=12.8%) had a medium-sized (approximately 200+/-15 microm2) perikaryon with 3-5 varicose dendrites, whereas others (x =35.5%, S.D.=14.0%) had a smaller (approximately 140+/-15 microm2) perikaryon with 3-4 varicose dendrites. There was a small number (x =6.5%, S.D.=8.5%) of larger DA neurons (209-584 microm2) with spiny dendrites and a few TH-immunoreactive cells displaying mixed neuron-glia morphology. Despite significant inter-individual variations in neuron density, the human striatum (mean volume of 8.76 cm3) harbored a mean of 331.9 DA neurons (S.D.=199.2). A prolific zone, containing about 3000 cells, occurred in the ventral striatum in two brains. The addition of these cells would increase by about 10 times the total number of striatal DA neurons, which should not be confounded with segments of nigrostriatal DA fibers that displayed large (8-12 microm) varicosities and looked like small bipolar neurons. The function of striatal DA neurons is unknown but the fact that their number increases markedly following lesion of nigral DA input or administration of various growth factors, opens up new therapeutic avenues for treatment of Parkinson's disease.
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PMID:Morphology and distribution of dopaminergic neurons intrinsic to the human striatum. 1558 97

The protein alpha-synuclein is implicated in the development of Parkinson's disease. The molecule forms Lewy body aggregates that are hallmarks of the disease, has been associated with the spread of neuropathology from the peripheral to the CNS, and appears to be involved with the autonomic disorders responsible for the gastrointestinal (GI) symptoms of individuals afflicted with Parkinson's. To characterize the normative expression of alpha-synuclein in the innervation of the GI tract, we examined both the postganglionic neurons and the preganglionic projections by which the disease is postulated to retrogradely invade the CNS. Specifically, in Fischer 344 and Sprague-Dawley rats, immunohistochemistry in conjunction with injections of the tracer Dextran-Texas Red was used to determine, respectively, the expression of alpha-synuclein in the myenteric plexus and in the vagal terminals. Alpha-synuclein is expressed in a subpopulation of myenteric neurons, with the proportion of positive somata increasing from the stomach (approximately 3%) through duodenum (proximal, approximately 6%; distal, approximately 13%) to jejunum (approximately 22%). Alpha-synuclein is co-expressed with the nitrergic enzyme nitric oxide synthase (NOS) or the cholinergic markers calbindin and calretinin in regionally specific patterns: approximately 90% of forestomach neurons positive for alpha-synuclein express NOS, whereas approximately 92% of corpus-antrum neurons positive for alpha-synuclein express cholinergic markers. Vagal afferent endings in the myenteric plexus and the GI smooth muscle do not express alpha-synuclein, whereas, virtually all vagal preganglionic projections to the gut express alpha-synuclein, both in axons and in terminal varicosities in apposition with myenteric neurons. Vagotomy eliminates most, but not all, alpha-synuclein-positive neurites in the plexus. Some vagal preganglionic efferents expressing alpha-synuclein form varicose terminal rings around myenteric plexus neurons that are also positive for the protein, thus providing a candidate alpha-synuclein-expressing pathway for the retrograde transport of putative Parkinson's pathogens or toxins from the ENS to the CNS.
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PMID:Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: autonomic pathway implicated in Parkinson's disease? 1840 22

Dysfunction of the microtubule (MT) system is an emerging theme in the pathogenesis of Parkinson's disease. This study was designed to investigate the putative role of MT dysfunction in dopaminergic neuron death induced by the neurotoxin 1-methyl-4-phenylpiridinium (MPP(+)). In nerve growth factor-differentiated PC12 cells, we have analyzed post-translational modifications of tubulin known to be associated with differently dynamic MTs and show that MPP(+) causes a selective loss of dynamic MTs and a concomitant enrichment of stable MTs. Through a direct live cell imaging approach, we show a significant reduction of MT dynamics following exposure to MPP(+) and a reorientation of MTs. Furthermore, these alterations precede the impairment of intracellular transport as revealed by changes in mitochondria movements along neurites and their accumulation into varicosities. We have also analyzed activation of caspase 3 and mitochondrial injury, well-known alterations induced by MPP(+), and found that they are noticeable only when MT dysfunction is already established. These data provide the first evidence that axonal transport impairment and mitochondrial damage might be a consequence of MT dysfunction in MPP(+) -induced neurodegeneration, lending support to the concept that alterations of MT organization and dynamics could play a pivotal role in neuronal death in Parkinson's disease.
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PMID:Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP+ -induced neurodegeneration. 2064 48

The histaminergic system fulfills a major role in the maintenance of waking. Histaminergic neurons are located exclusively in the posterior hypothalamus from where they project to most areas of the central nervous system. The histamine H(3) receptors are autoreceptors damping histamine synthesis, the firing frequency of histamine neurons, and the release of histamine from axonal varicosities. It is noteworthy that this action also extends to heteroreceptors on the axons of most other neurotransmitter systems, allowing a powerful control over multiple homeostatic functions. The particular properties and locations of histamine H(3) receptors provide quite favorable attributes to make this a most promising target for pharmacological interventions of sleep and waking disorders associated with narcolepsy, Parkinson's disease, and other neuropsychiatric indications.
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PMID:Histamine H3 receptors and sleep-wake regulation. 2086 2


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